The long term objective is to understand the function of the oxygen carriers myoglobin, and hemoglobin, in terms of structure at an atomic level. Function will be assessed by measurements of kinetics of ligand rebinding using flash photolysis to cover a time range from tens of picoseconds to milliseconds. At the shortest times after photolysis the ligand is still in the protein, and its behavior may be regarded as a probe of the structure of the heme pocket. Molecular dynamics simulations will be employed as an interpretative tool. The work proposed is an element in a wider collaborative whole in which site-directed mutagenesis will be used to prepare specific mutants whose 3-D structure will be determined by x-ray crystallography. Human hemoglobin is a tetramer containing two types of subunit, and as a result, the effects of single-site mutations are diluted by the native subunit. This problem will be met by the use of hybrid hemoglobins with specific hemes replaced by nickel or cobalt porphyrins, and by specific substitution of hemes such as meso- and deuterohemes for protoheme. The immediate relation to health is to advance the design of oxygen- carrying proteins for use as substitutes for blood in transfusion. More widely, the systems are sufficiently characterized to offer a unique opportunity to assess the effectiveness of molecular dynamics simulations in predicting the behavior of macromolecules, and hence contribute to rational drug design.